The present invention relates to novel methods of using known pharmacological agents. These novel methods are to be used in the treatment of conditions or symptoms due to certain disease conditions in mammals. In particular this invention relates to a novel method of inhibiting the formation of products of the "arachidonic acid cascade" in such pathological states. This inhibition is accomplished by inhibiting the action of the enzyme phospholipase A.sub.2, an important mediator in the cascade, by administering certain butyrophenones.
The important role of phospholipase A.sub.2 in mammalian metabolism through the formation of prostaglandins is now well known. See W. Vogt, Advances in Prostaglandin and Thromboxane Research, Vol. 3, page 89, (1978); P. C. Isakson, et al., Advances in Prostaglandin and Thromboxane Research, Vol. 3, page 113, (1978). Phospholipase A.sub.2 is responsible for the hydrolysis of arachidonic acid-containing phospholipids, thereby providing substrate for the multiple enzymes of the arachidonic acid cascade.
The products of the arachidonic acid cascade are varied. While generally the products of the cascade are beneficial, in certain disease processes and other conditions the production of prostaglandins and similar products induces deleterious consequences such as inflammation (see paper by N. A. Plummer et al., abstracted in Journal of Investigative Dermatology, Vol. 68, No. 4, p. 246 (1977)); erythema (N. A. Plummer, supra); platelet aggregation (B. B. Vargaftig, J. Pharm. Pharmacol., Vol. 29, p. 222-228 (1977)); and the release of SRS-A (slow reacting substance-anaphylaxis), a known mediator of allergenic responses. The inhibition of phospholipase A.sub.2 prevents these and similar conditions mediated by the action of this enzyme.
The butyrophenones of this invention are known hypotensive agents. They are prepared by conventional means. These compounds have been found surprisingly and unexpectedly to inhibit phospholipase A.sub.2.